Neurosensory system

11/8/2019 Dr Kavita Karmacharya
Neurosensory System
• Dr Kavita Karmacharya

Cellular Pathology of Central
Nervous system

Reactions of Neurons to Injury

Normal neurons cerebral cortex

Acute neuronal injury (red neurons)
• Changes due to acute CNS hypoxia/ischemia
• Reflect cell death - Necrosis/apoptosis
• Evident with H & E preparations
– at about 12-24 hrs after an irreversible hypoxic or
ischemic insult
• Morphology
– Shrinkage of cell body
– Pyknosis of nucleus
– Disappearance of nucleolus
– Loss of Nissl substance
– Intense eosinophilia of cytoplasm

Subacute and chronic neuronal injury
(degeneration)
• Neuronal death – d/t progressive disease process
of some duration
• Occurs in certain slowly evolving neurologic
diseases
– Amyotrophic lateral sclerosis (ALS)
• Histologic features :
– Cell loss (neurons)
– Reactive gliosis

Axonal reaction
• Reaction within cell body that attends
regeneration of axon
• Best seen in anterior horn cells of spinal cord
when motor axons are cut or seriously
damaged
• Increased protein synthesis
– associated with axonal
sprouting

Subcellular alterations in neuronal organelles &
cytoskeleton
• Neuronal inclusions d/t
– aging or
– genetically determined disorders of metabolism
• Intracytoplasmic accumulations of complex lipids
(lipofuscin), proteins or carbohydrates
– Viral infection
• Intranuclear inclusions (cowdry body)
–herpetic infection
• Cytoplasmic inclusions (Negri body)
–rabies
• Both nucleus and cytoplasm inclusions
–CMV infection

Negri body

Degenerative diseases of CNS
• Neuronal intracytoplasmic inclusions
– Neurofibrillary tangles – Alzheimer disease
– Lewy bodies – Parkinson disease
• Proteinopathies
– Contain proteins with altered conformation
– Result from mutation – that affect protein folding,
ubiquitination and intracellular trafficking

Neurofribllary tangles
Silver stain

Normal substantia
nigra
Depigmented
substantia nigra
Lewy body –
bright pink in
substantia
nigra neuron

Reactions of Astrocytes to Injury

Astrocytes
• Star-shaped appeaarance
• Multipolar, branching cytoplasmic processes
that emanate from the cell body
• Contains – glial fibrillary acidic protein
(GFAP)
• Act as metabolic buffers and detoxifiers within
brain
• Foot processes surrounds the capillaries
– Contribute to barrier functions – controlling the
flow of macromolecules between blood, CSF and
brain -

Reactions
• Gliosis (astrogliosis)
– Most important histopathologic indicator of CNS
injury
– Hypoxia/ hypoglycemia and toxic injuries

Normal astrocytes Reactive astrocyties
• Hypertrophy and
hyperplasia of astrocytes
Nuclei
• Typically round to oval
• Evenly dispersed , pale
chromatin
• Enlarged nuclei
• Vesicular nuclei
• Prominent nucleoli
Cytoplasm
• Scant cytoplasm
• Bright pink abundant
cytoplasm
• Irregular cytoplasm which
swath around eccentric
nucleus
• Numerous stout/ramifying
processes appear –
gemistocytic astrocytes

11/8/2019 Dr Kavita KarmacharyaReactive Gliosis necrosis

Long standing gliosis
• Rosenthal fibers
– Thick elongated, brightly eosinophilic, irregular strs
– Pilocytic astrocytoma
• Degenerating changes of astrocytes
– PAS positive corpora amylacea or polyglucosan
bodies
– Round/ faintly basophilic
– Located wherever there are astrocytic end processes
– Esp in perivascular zones

Reactions of other glial cells to injury
• Oligodendroglial cells
–Apoptosis
• Demyelinating disorders
• Leukodystrophies
–Viral inclusion in oligodendroglial nuclei
• Progressive multifocal leukoencephalopathy

• Ependymal cells
– Do not have specific patterns of reactions
– Marked inflammation or dilation of ventricular
system
• Disruption of ependymal lining + astrocytic
proliferation
– CMV –may produce viral inclusions in ependymal
cells

Reactions of microglia to injury

Microglia
• Mesoderm derived cells
• Primary function
– To serve as a macrophage in CNS
– Share many surface markers with peripheral
monocytes/ macrophages

• Respond to injury by
(1) proliferating
(2) developing elongated nuclei (rod cells)
– neurosyphilis
(3) forming aggregates about small foci of
tissue necrosis
– microglial nodules
(4) congregating around cell bodies of dying
neurons
– neuronophagia

11/8/2019 Dr Kavita KarmacharyaMicroglial nodules in HIV enchephalitis

Meningitis
• Dr Kavita Karmacharya

• Inflammatory process of the leptomeninges
and CSF within subarachnoid space
• Meningoencephalitis – combines meningitis
with inflammation of brain parenchyma

• Infectious
– Bacterial meningitis – acute pyogenic
– Viral meningitis – aseptic meningitis
– Tubercular meningitis – chronic meningitis
– Fungal meningitis – cryptococcal meningitis
• Non-infectious
– Nonbacterial irritant introduced into the
subarachnoid space
– Chemical meningitis

Acute Bacterial Meningitis

• Acute purulent infection within subarachnoid
space
• Associated with CNS inflammatory reaction
– Decreased onsciousness
– Raised intracranial pressure (ICP)
– Stroke
• Meninges / subarachnoid space/ brain
parenchyma are all frequently involved in
inflammatory reaction
– meningoencephalitis

Epidemiology
• Most common form of suppurative CNS
infection
• Annual incidence U.S. > 2.5 cases/100,000
population
• Recently – incidence has declined dramatically
– d/t increased use of antibiotics and vaccines
for the organisms causing it

Etiology
• Streptococcus pneumoniae
• Niesseria meningitidis
• Enteric gram-negative bacilli
• Group B streptococcus / S. agalactiae
• Listeria monocytogenes
• H. influenzae
• Streptococcus aureus
• Coagulase-negative staphylococci

Pathophysiology
S.Pneumoniae and N. Meningitidis
↓
Initially colonize nasopharynx by attaching to
nasopharyngeal epithelial cells
↓
Bacteria are transported across epithelial cells in
membrane-bound vacuoles to intravascular
space
↓

In bloodstream, bacteria are able to avoid
phagocytosis
• by neutrophils and classic complement-
mediated bactericidal activity
• because of polysaccharide capsule
↓
Reach intraventricular choroid plexus
↓
Infects choroid plexus epithelial cells
↓
Gain access to the CSF because of absence of
effective host immune defences

Normally CSF contains few WBCs and
relatively small amounts of complement
proteins and Ig
↓
No opsonization of bacteria
↓
No phagocytosis of bacteria
↓
Inflammatory response induced by invading
bacteria
↓

Multiplication of bacteria and lysis of bacteria d/t
antibiotic therapy
↓
Subsequent release of cell-wall components :
• Lipopolysaccharide – gram negative bacteria
• Teichoic acid/peptidoglycans – S. Pneumoniae
↓
Produces cytokines and chemokines by
Microglia/astrocytes/monocytes/microvascular
endothelial cells & CSF leukocytes
↓

Cytokines (TNF, IL-1)
↓
Increase permeability of BBB
↓
Vasogenic edema and leakage of serum proteins
into subaracnoid space
↓
Increase in CSF protein concentration and
leukocytosis
↓
Inflammation of meninges  Meningitis

Pathophysiology

Clinical features
• Acute fulminant illness  progresses rapidly
in a few hours
• Subacute infection  progressively worsens
over several days
• Classic Triad of meningitis
–Fever
–Headache
–Nuchal rigidity

• Decreased level of consciousness
• Nausea
• Vomiting
• Photophobia
• Seizures

Diagnosis
• Blood cultures
– s/be immediately taken
– Empirical antimicrobial therapy initiated without
delay
• Examination of CSF
– Performing Lumbar puncture without delay

Cerebrospinal Fluid (CSF) Abnormalities in Bacterial Meningitis
Opening pressure >180 mmH2O
White blood cells 10/L to 10,000/L; neutrophils predominate
Red blood cells Absent in nontraumatic tap
Glucose <2.2 mmol/L (<40 mg/dL)
CSF/serum glucose <0.4
Protein >0.45 g/L (>45 mg/dL)
Gram's stain Positive in >60%
Culture Positive in >80%
Latex agglutinationMay be positive in patients with meningitis
due to S. pneumoniae, N. meningitidis, H.
influenzae type b, E. coli, group B
streptococci
PCR Detects bacterial DNA

Treatment
• Empirical antimicrobial therapy
• Specific antimicrobial therapy
• Adjunctive therapy
• Treatment of increased intracranial pressure

Morphology
• Exudate within leptomeninges over the surface
of brain
• Meningeal vessels engorged and stand out
prominently
• If meningitis is fulminant  the infection may
extend to the ventricles  ventriculitis

Microscopic examination
• Neutrophils fill
– Subarachnoid space
– Around leptomeningeal blood vessels
• Gram stain
– Variable causative organisms

Acute viral meningitis

Clinical manifestations
• Headache
– Frontal/retro-orbital
– Associated with photophobia
– Pain on moving the eyes
• Fever
• Signs of meningeal irritation
– Nuchal rigidity - mild

• Constitutional signs
– Malaise
– Myalgia
– Anorexia
– Nausea
– Vomiting
– Abdominal pain
– Diarrhoea
– Lethargy
– drowsiness

EtiologyViruses Causing Acute Meningitis and Encephalitis
Acute Meningitis
Common Less Common
Enteroviruses
(coxsackieviruses,
echoviruses, and
human
enteroviruses 68–71)
Varicella zoster virus
Herpes simplex virus
2
Epstein-Barr virus
Arthropod-borne
viruses
Lymphocytic choriomeningitis virus
HIV

Laboratory diagnosis
Cerebrospinal Fluid (CSF) Abnormalities in Viral
Meningitis
Opening pressure 100–350 mm H2O
White blood cells 25–500 cells/L; lymphocyte
predominate
Red blood cells Absent in nontraumatic tap
Glucose Normal glucose concentration
CSF/serum
glucose
<0.4
Protein 20–80 mg/dL
Gram's stain/ZN No organisms
Culture Negative
PCR Detects viral nucleic acid

Treatment
• Symptomatic treatment
– Analgesics
– Antipyretics
– Antiemetics
• Oral or intravenous acyclovir
– HSV-1 or 2
– EBV or VZV
• IVIg – deficient humoral immunity

Prevention
• Vaccination
– Live attenuated VZV vaccine (Varivax)

Tuberculous meningitis

Occurs most commonly shortly after a primary
infection in childhood
Or
As a part of miliary tuberculosis
• Usual local source of infection
– Caseous focus in the meninges or brain substance
adjacent to CSF pathway

• Brain is covered by
– Greenish , gelatinous exudate
– Especially around the base
– Numerous scattered tubercles are found on
meninges

Investigations
• CSF is under increased pressure
• Grossly
–Clear
–When allowed to stand
• Fine clot (‘spider web’)
–Cells
• 500 cells/cumm
• lymphocytes

• Centrifuged deposit smear from CSF
– Tubercular bacilli
• CSF – cultured for AFB bacilli
– But the result will not be known for upto 6 weeks
– Treatment must be started without waiting for
confirmation
• Brain imaging
– Hydrocephalus
– brisk meningeal enhancement on enhanced CT
– Intracranial tuberculoma

Management
• Antitubercular therapy
• Maintain adequate hydration and nutrition

Other forms of meningitis

Fungal meningitis (cryptococcosis)
• Immunosuppressed patients
• Complication of HIV infection
• CSF findings – similar to tuberculous
meningitis
• Diagnosis is confirmed by microscopy or
specific serological tests

Condition Cell type Cell
count
Glucose Protein Gram
stain
Normal Lymphocytes <5 per
cumm
>60% of
blood
glucose
15-45 mg/dl -
Viral Lymphocytes 10-2000 Normal Normal -
Bacterial Polymorphs 1000-
5000
Low Increased +
Tuberculo
sis
Polymorphs/
lymphocytes
/mixed
50-5000 Low Elevated -
(ZN
stain
+ve)
Fungal Lymphocytes 50-500 Low Elevated +/-

Viral encephalitis

• Range of viruses can cause encephalitis
• Only minority of patients have history of
recent viral infection
• Causes of viral encephalitis
– Herpes simplex  reaches the brain via olfactory
nerves (most common cause)
– Viruses trasmitted by mosquitoes and ticks
(arboviruses)
– HIV infection – manifestation of AIDS

Pathology
• Inflammation occurs inn the cortex/ white
matter/ basal ganglia / brain stem
• Herpes simplex encephalitis
– Temporal lobes primarily affected
– Inclusion bodies – neurons/ glial cells
– Infiltration of polymorphonuclear cells in
perivascular space
– Neuronal degeneration
– Diffuse glial proliferation
– Cerebral oedema

Clinical features
• Acute onset of headache
• Fever
• Focal neurological signs
– aphasia and/or hemiplasia
• Seizures
• Disturbance of consciousness
– Drowsiness
– Deep coma

Investigations
• CT scan
– Mass lesion should be excluded first
– Herpes simplex encephalitis
• Low-density lesions in temporal lobes
• CSF
– Excess lymphocytes
– PMN may predominate in early stages
– Protein may be elevated
– Glucose is normal

• EEG
– Abnormal in early stages
– Periodic slow wave activity in temporal lobes –
herpes simplex encephalitis
• PCR
– Reveal causative oraganism

Management
• Anticonvulsant treatment
• Increased ICT  dexamethasone
• Acyclovir

Poliomyelitis

Causes
• Polioviruses
• Still a major problem in developing world
• Oral vaccines – lesser prevalence
• Infection usually occurs through the
nasopharynx

• Virus causes lymphocytic meningitis
• Infects grey matter of the spinal cord/ brain
stem and cortex
• Particular propensity to damage anterior horn
cells esp in lumbar segment

Clinical features

• Incubation period – 7 -14 days
• Many patients recover fully after the initial
phase of few days of mild fever and headache
• In others – after a week of well being
– Recurrence of pyrexia, headache and meningism
– Weakness may start later in one muscle group and
progress to widespread paresis
• Respiratory failure may supervene if
intercostal muscles are paralysed or the
medullary motor nuclei are involved

Investigations
• CSF
– Lymphocytic pleocytosis
– Rise in protein
– Normal sugar content
• Poliomyelitis virus may be cultured from CSF
and stool

Management
• Early stages
– Bed rest
• Respiratory difficulties
– Tracheostomy and ventilation
• Subsequent treatment
– Physiotherapy
– Orthopaedic measures

Progressive Multifocal
Leucoencephalopathy

• More frequently occurs as a feature of AIDS
• Infection of brain oligodendrocytes by human
polyomavirus JC
• Widespread demyelination of white matter of
cerebral hemisphere

Clinical signs
– Dementia
– Hemiparesis
– Aphasia
• Progresses rapidly leading to death within
weeks or months

Neurosensory system

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